EP1408956A1 - Uses of metal salts to stabilize taxane-based compositions - Google Patents
Uses of metal salts to stabilize taxane-based compositionsInfo
- Publication number
- EP1408956A1 EP1408956A1 EP01920712A EP01920712A EP1408956A1 EP 1408956 A1 EP1408956 A1 EP 1408956A1 EP 01920712 A EP01920712 A EP 01920712A EP 01920712 A EP01920712 A EP 01920712A EP 1408956 A1 EP1408956 A1 EP 1408956A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- acid
- composition
- carrier
- taxane
- paclitaxel
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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- 229910052751 metal Inorganic materials 0.000 title claims abstract description 52
- 239000002184 metal Substances 0.000 title claims abstract description 52
- 150000003839 salts Chemical class 0.000 title claims abstract description 50
- 229940123237 Taxane Drugs 0.000 title claims abstract description 47
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- 238000000034 method Methods 0.000 claims abstract description 18
- 239000002253 acid Substances 0.000 claims abstract description 17
- 238000003860 storage Methods 0.000 claims abstract description 5
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- 230000002588 toxic effect Effects 0.000 description 1
- WEAPVABOECTMGR-UHFFFAOYSA-N triethyl 2-acetyloxypropane-1,2,3-tricarboxylate Chemical compound CCOC(=O)CC(C(=O)OCC)(OC(C)=O)CC(=O)OCC WEAPVABOECTMGR-UHFFFAOYSA-N 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- 229960004799 tryptophan Drugs 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- DNYWZCXLKNTFFI-UHFFFAOYSA-N uranium Chemical compound [U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U] DNYWZCXLKNTFFI-UHFFFAOYSA-N 0.000 description 1
- 235000014393 valine Nutrition 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
- 229910001845 yogo sapphire Inorganic materials 0.000 description 1
- 239000010457 zeolite Substances 0.000 description 1
- 229910000368 zinc sulfate Inorganic materials 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
- A61K38/13—Cyclosporins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/28—Compounds containing heavy metals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K31/355—Tocopherols, e.g. vitamin E
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- TWEEN TM polyoxyethylated sorbitan esters ICI Wilmington, DE
- SOFTIGEN TM polyethylene glycol esters of caprylic and capric acids H ⁇ ls AG
- modified castor oils including polyoxyethylated or hydrogenated castor oils (such as CREMOPHOR TM EL, EP-P or RH 40) (BASF, Mt.
- the surface absorption for pinewood charcoal is 1,000 m 2 /g and 650 m 2 /g for peat charcoal.
- the activated charcoal has a surface area ranging from about 500 to about 1300 m /g (including sub-ranges thereof), and preferably a median surface area range of about 900 m /g.
- taxane carriers such as castor oils with charcoal is described in International patent publication WO 00023070.
- Standard reference works setting forth the general principles of pharmacology include Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9 Ed., McGraw Hill Companies Inc., New York (1996). Standard reference works setting forth the general principles of modern pharmaceutics (Remington's Pharmaceutical Sciences, 18 th Ed., Gennaro, Mack Publishing Co., Easton, PA (1990) and Remington: The Science and Practice of Pharmacy, Lippincott, Williams & Wilkins (1995)).
- the following examples are intended to further illustrate certain preferred embodiments of the invention and are not limiting in nature.
- EXAMPLE 1 Stability Tests of Paclitaxel in Pretreated Cremophor EL The stabilizing effect of coordinating metal salts, such as zinc, copper and ferrous sulfate or gluconate, on paclitaxel in an EtOH/EL (50:50) formulation (6 mg/mL) was examined. Salt columns were used to treat Cremophor EL before being added to paclitaxel formulations, which was then analyzed after being subjected to stress (24 hours at 80°C).
- coordinating metal salts such as zinc, copper and ferrous sulfate or gluconate
- Paclitaxel composition containing Cu 2+ Gluconate, Fe 2+ Gluconate, Ca 2+ Ascorbate, FeSO , A.A 6-Palmitate, or HOCH 2 SO 2 Na was prepared in the same way.
- the paclitaxel samples and the control were subjected to 80°C for 24 hours. Then the paclitaxel degradation was tested.
- the paclitaxel stability tests results are shown in Table 2.
- the paclitaxel formulation containing Ascorbyl 6-Palmitate was prepared by adding Ascorbyl 6-Palmitate to the control formulation.
- the stability test results were listed in Table 4.
- Ascorbyl palmitate (5 mg) added as an ethanol solution to the paclitaxel formulation.
- the data in Table 4 show that in the presence of Ascorbyl 6-Palmitate, paclitaxel degradation is less than 1% after being exposed to a temperature of 80°C for 24 hours. In the absence of Ascorbyl 6-Palmitate, paclitaxel degradation in the formulation is more than 34% after being exposed to the same condition.
- Cremophor El (-400 mL) was pumped through a steel column containing activated charcoal (34 g) at a flow rate of approximately 0.2 mlVmin. The initial eluate (-20 mL) was discarded and the successive fraction (-45 mL) was collected and subsequently passed through a second steel column containing FeSO (18 g). The initial eluate was discarded (-20 mL) and the remainder of material was used to prepare the Paclitaxel formulation for stability analysis.
Abstract
Disclosed are compositions containing a taxane, a carrier and a metal salt of an acid. Also disclosed are methods of stabilizing taxane/carrier compositions and reducing degradation of taxanes e.g., during storage. The methods entail including the metal salt in the taxane composition or pretreating the carrier with the metal salt, optionally in combination with other pretreatments.
Description
USES OF METAL SALTS TO STABILIZE TAXANE-BASED COMPOSITIONS
PRIORITY This application claims the priority of U.S. Provisional Application No. 60/191,802, filed March 24, 2000, the contents of which are hereby incorporated by reference. BACKGROUND OF THE INVENTION
Taxol (paclitaxel) is a compound extracted from the bark of a western yew, Taxus brevifolia and known for its antineoplastic activity. Since 1977, taxol has been tested and used as an antineoplastic agent because of its unique mechanism of action and good cytotoxic activity against IP implanted D16 melanoma and the human X-l mammary tumor xenograft. Paclitaxel has been widely used in treating ovarian and breast cancer. It has also been shown to be effective against other types of cancer, such as melanoma, lymphoma, and those developed in the lung, head and neck. The scientific literature is replete with reports of the efficacy of paclitaxel in the treatment of a variety of unrelated conditions (see for example, Einzig et al, Proc. Am. Soc. Clin. Oncol., 20:46 (1996) for lung cancer and head and neck carcinomas; Forastire et al. Sem. Oncol., 20:56 (1990) for neoplasms in the skin; Chang et al, Cancer 77 (1):14-18 (1996) for gastric cancer) and Woo et al, Nature, 368:750 (1994) for polycystic kidney disease; and (Pouvelle et al, J. Clin. Invest. 44:413-417 (1994)) for malaria.
Preclinical studies have suggested that paclitaxel alone is not absorbed after oral doses. For example, Walle et al. observed that taxol is not absorbed after oral administration, and attributed the low oral bioavailability of taxol to the action an outwardly directed efflux pump (Drug Metabol. Disp. 26: (4): 343 -346 (1998)). Suffness et al. observed that paclitaxel is very poorly absorbed and the absorption is less than 1% when administered orally. Thus, Suffness et al. concluded that oral dosing with paclitaxel did not seem possible. (Taxol Science and Applications, CRC Press (1995)). Similarly, Eiseman et al. indicates that paclitaxel has a bioavailability of 0% upon oral administration (Second NCI Workshop on Taxol and Taxus (Sept. 1992)).
Accordingly, efforts have been directed to other modes of administration, such as intravenous injection ("IN"). However, taxol exhibits poor solubility in aqueous solution. One approach to address the poor solubility of taxanes such as paclitaxel has been to seek excipients which increase the solubility of paclitaxel. Thus, most paclitaxel formulations for IN administration have been developed utilizing a surfactant, such as polyethoxylated castor oil which is commercially available as CREMOPHOR EL™, as a drug carrier. Polyethoxylated castor oils are commonly used as solubilizing and/or dispersing agents for a variety of pharmaceutically active agents that are substantially insoluble in water. However, the use of surfactants in the formulation compromises the stability of paclitaxel. Impurities tend to catalyze the decomposition of the pharmaceutically active agents, particularly antineoplastic agents such as paclitaxel. In particular, it has been found that pharmaceutical compositions of paclitaxel in a co-solvent system containing dehydrated ethyl alcohol and commercial grade Cremophor EL® exhibit a loss of potency of greater than 60% after storage for 12 weeks at 50°C, the loss of which is attributable to the decomposition of paclitaxel during storage. In addition to the impurities such as colorants and dopants that are contained in the castor oil solution that is used to prepare the pharmaceutical composition, other impurities are formed during storage of the ultimate pharmaceutical formulation. Such impurities include fibrous precipitate of unknown composition, and which also cause loss of potency of the active agent. Various attempts have been made to increase paclitaxel stability in IN formulations.
Aluminum oxide and magnesium silicates have been used to eliminate carboxylate anions from Cremophor. See WO 98/30205. Acidifying agents have also been tested for increasing taxol stability. See U.S. Patent 5,977,164. Agharkar, et al, U.S. Patent 5,504,102 discloses treating a polyoxyethylated castor oil with an acid or contacting with alumina to reduce the carboxylate anion content. The low carboxylate anion content of the solvent is believed to provide extended shelf life and lower amounts of degradation by-products.
International patent publication WO 00023070 is directed to a method of purifying polyethoxylated castor oils using a combination of an activated carbon column and an ion exchange resin column. ZA 9903053 to Schein Pharmaceutical, Inc. teaches a
polyethoxylated castor oil with low cation content ("lcp-castor oil"), wherein the cation concentrations are no greater than Al (20), K (20), Na (12) and Ca (80), expressed in ppm. The lcp-castor oil is purified by contacting an untreated or partially treated polyethoxylated castor oil with an activated cationic exchange resin. Nikolayev, et al., U.S. Patent 5,925,776, also teaches a low cation content polyethoxylated castor oil prepared by contacting the polyethoxylated castor oil with a strong cation exchange resin such as sulfonated divinylbenzene-styrene copolymer.
Dralle-Nass, et al, U.S. Patent 5,925,776, is directed to a method of purifying alkoxylated fats such as Cremophor with a mixture of alumina and silicate (e.g., Mg, Ca or Al) solids followed by filtration. In preferred embodiments, a paclitaxel-containing solution is contacted with a molecular sieve material, preferably porous Al2O3 (or zeolite) having a particle size of 5-200 microns and a pore size of up to about 150 angstroms.
EP 674510 Bl to Napro Biotherapeutics teaches a composition of taxol and polyethoxylated castor oil having a pH less than 8.1. The pH balance reportedly improves stability. In preferred embodiments, citric acid is used to adjust the pH value.
There remains a need to develop additional stable compositions and effective methods suitable for IN administration of paclitaxel and other taxanes. Such IN formulations should be capable of achieving target therapeutic blood levels of taxane and be suitable to maintain the taxane in solution. The IN formulations should also be chemically stable over extended periods of time, and possess overall palatability while demonstrating long term stability. BRIEF SUMMARY OF THE INVENTION
The present invention provides compositions containing a taxane and a carrier stabilized with at least one metal salt of an acid. In preferred embodiments, the acid is gluconic acid, an amino acid, ascorbic acid, palmitic acid, citric acid, an alpha or a beta hydroxy acid, sulfuric acid, alpha-hydroxymethylsulfinic acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid, benzoic acid, or sulfonic acid, and the metal is iron, copper, zinc, calcium, manganese, magnesium, aluminum, tin, lanthanum, platinum, cerium, or titanium. In more preferred embodiments, the metal salt is zinc methionine, sodium hydroxymethylsulfinate or an iron, copper, zinc, calcium, manganese, magnesium, aluminum,
or titanium gluconate or hydroxymethylsulfinate. In yet other preferred embodiments, the carrier contains both a polyethoxylated castor oil such as Cremophor and a co-solubilizer such as vitamin E TPGS.
The presence of the metal salt in the taxane composition provides enhanced stability. In another aspect of the present invention, the stabilized taxane compositions are prepared by contacting the castor oil and the metal salt prior to the addition of the taxane. In preferred embodiments, the metal salt and castor oil are mixed together and then heated, or the castor oil is applied to a column containing the metal salt. In other preferred embodiments, the castor oil is contacted with activated charcoal in a separate step. Without intending to be bound by any particular theory of operation, it is believed that the metal salt stabilizes the taxane by inhibiting or protecting against solvolysis of the ester side chain at C-13, deacetylation at C-10 and/or epimerization at C-7 (compared to solvolysis, deacetylation and epimerization at the same positions of the taxane in a composition comprising the taxane and the castor oil but not the metal salt). DETAILED DESCRIPTION OF THE INVENTION
The term "taxane" as used herein identifies a diterpene moiety that is only slightly soluble in water. Taxanes according to the invention include, without limitation moieties isolated from the Pacific yew tree (Taxus brevifolia) and purely synthetic taxanes. Preferably, the taxane is selected from the group consisting of paclitaxel, docetaxel, derivatives, metabolites, analogs and prodrugs of paclitaxel or docetaxel, and salts, polymorphs and hydrates thereof. More preferably, the taxane comprises paclitaxel. In some embodiments of the invention, more than one taxane is included as active ingredient. The taxane concentration in the formulations of the present invention may vary based on the carrier(s), co-solubilizer(s) and/or metal salts and on the desired total dose of taxane to be administered intravenously to a mammal. In general, the concentration of taxane in the compositions ranges from about 2 to about 100 mg/ml, preferably from about 6 to about 60 mg/ml or more, preferably from about 10 to about 50 mg/ml.
The metals are non-toxic and can be found in Martindale - The Extra Pharmacopeia, James E.F. Reynolds, Ed., The Pharmaceutical Press, London, the content of which is
incorporated herein by reference. The metals include, but are not limited to copper (Cu++), magnesium (Mg++), zinc (Zn++), calcium (Ca++), iron (Fe++ and Fe+++), aluminum (Al+++), cobalt (Co++), titanium (Ti+++ and Ti +), platinum (Pt**), lanthanum (La+++), cerium (Ce^"" and Ce4+), selenium (Se4+), and manganese (Mn++). Suitable acids include amino acids, ascorbic acid, saturated or unsaturated fatty acids such as palmitic acid, alpha and beta hydroxy acids, e.g. gluconic acid and citric acid, sulfuric acid, alpha-hydroxymethylsulfinic acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid, benzoic acid, selenious acid, and sulfonic acid. Examples of amino acids include naturally occurring amino acids such as glycine, alanine, leucine, isoleucine, phenylalanine, tryptophan, aspartic acid, glutamic acid, methionine, threonine, valine, lysine, arginine, serine, histidine, proline, glutamine, methionine and asparagine, and synthetic non-naturally occurring amino acids. Methionine is a preferred amino acid; zinc methionine is a preferred metal salt. Synthetic amino acids include derivatives of the naturally occurring amino acids such as N-alkylated or N-hydroxy-alkylated amino acids. Other preferred metal salts include iron, copper, zinc, calcium, manganese, magnesium, aluminum, or titanium gluconate or hydroxymethylsulfinate. However, arsenates, cyanates and other toxic metal salts can not be used in the present taxane formulation. In general, amounts of the metal salt effective to provide increased stability of the taxane range from about 0.2% to about 5% of the composition by weight. A preferred range is from about 0.4% to 3% and a more preferred range is from about 0.6% to about 2%.
Applicants have found that not all metal salts provide effective stabilization of the taxane. Mercury, cadmium, uranium, lead, lithium and barium salts are not useful. In addition, sodium hydroxymethylsulfinate was proven to be an effective stabilizer but other sodium salts were relatively ineffective. For purposes of the invention, the term "carrier" is used to denote a moiety that maintains (and in preferred embodiments improves) the aqueous solubility of the taxane in the pharmaceutical composition of the invention. Carriers according to the instant invention include without limitation moieties which may also function as co-solubilizers. The carriers of the invention are characterized by a core structure that may be either a straight chain
polyether or a branched glycol (e.g., glycol) coupled with at least one fatty acid ester. Preferred carriers for use in the invention are non-ionic surfactants or emulsifiers having HLB values of at least about 10. It has been found that such non-ionic surfactants or emulsifiers are not only compatible carriers for the lipophilic taxanes (which are poorly soluble in water) but also promote absorption of the active ingredient from the gastrointestinal tract into the bloodstream.
Representative examples of carriers according to the invention include Vitamin E TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate, available from Eastman Chemical Co., Kingsport, TN); saturated polyglycolyzed glycerides such as the GELUCIRE " and LABRASOL products (Gattefosse Corp., Westwood, NJ) which include glycerides of C8 - C18 fatty acids; CREMOPHOR™ EL or other modified castor oils including polyoxyethylated or hydrogenated castor oils such as EL-P or RH40 modified castor oils (available from BASF, Mt. Olive, NJ); MYRJ™ polyoxyethylated stearate esters (sold by ICI Americas, Charlotte, NC); TWEEN™ (ICI Americas) and CRLLLET ™ (available from Croda Inc., Parsippany, NJ) polyoxyethylated sorbitan esters; BRIJ™ polyoxyethylated fatty ethers (ICI Americas); CROVOL modified (polyethylene glycol) almond and corn oil glycerides, including polyethylene glycol almond or corn oil glycerides (Croda Inc., Edison, NJ); EMSORB™ sorbitan diisostearate esters (Henkel Corp., Ambler, PA); SOLUTOL™ polyoxyethylated hydroxystearates (BASF); and cyclodextrin. The castor oil is preferably is a polyethoxylated castor oil, or polyethoxylated castor oil derivatives. The pharmaceutical composition further comprises a dehydrated alcohol, preferably ethanol.
The term "co-solubilizer" is used to designate a viscosity-reducing moiety which increases the fluidity of the compositions of the invention at body temperature, as generally required for oral bioavailability, and/or reduce the melting point of the compositions below body temperature. Preferred co-solubilizers according to the invention decrease the viscosity and increase the fluidity of the vehicle at body temperature, and also may increase the amount of the active agent that can be dissolved or dispersed in the vehicle in comparison with the use of a carrier alone. Co-solubilizers according to the invention include moieties capable of
functioning as carriers as well. Co-solubilizers according to the instant invention include without limitation moieties that may also provide increased taxane solubility.
Representative non-limiting examples of viscosity-reducing co-solubilizers include PHARMASOLVE™ (N-methyl-2-pyrrolidone, International Specialty Products, Wayne, NJ); MIGLYOL™ glycerol or propylene glycol esters of caprylic and capric acids (Hϋls AG, Marl, Germany); polyoxyethylated hydroxystearates, including stearyl or oleyl ethers (e.g., SOLUTOL™ HS 15) (BASF, Mt. Olive, NJ); TWEEN™ polyoxyethylated sorbitan esters (ICI Wilmington, DE); SOFTIGEN™ polyethylene glycol esters of caprylic and capric acids (Hϋls AG); modified castor oils including polyoxyethylated or hydrogenated castor oils (such as CREMOPHOR™ EL, EP-P or RH 40) (BASF, Mt. Olive, NJ); vegetable oils such as olive oil, polyoxyethylated fatty ethers or modified castor oils; certain saturated polyglycolyzed glycerides, including glycerides of C8 - C18 fatty acids (such as a LABRASOL ); citrate esters such as tributyl citrate, triethyl citrate and acetyl triethyl citrate, propylene glycol, alone or in combination with PHARMASOLVE , ethanol (including dehydrated ethanol), water, and lower molecular weight polyethylene glycols such as PEG having a molecular weight in the range of 200 to 400 daltons, preferably PEG 200, PEG 300 and/or PEG 400. In a particularly preferred embodiment, the co-solubilizer is ethanol. In a more particularly preferred embodiment, the co-solubilizer comprises propylene glycol and ethanol. Up to 90% of the composition by weight may be co-solubilizer. In some embodiments of the invention, from about 10 to about 70% by weight is co-solubilizer. In preferred embodiments of the invention, the co-solubilizer is present in an amount of from about 20 to about 60% by weight. Accordingly, preferred pharmaceutical compositions may comprise from about 10% to about 70% by weight of propylene glycol, more preferably from about 20 to about 60% by weight of propylene glycol. In a particularly preferred embodiment the pharmaceutical composition of the invention comprises about 40% by weight of propylene glycol.
In a particularly preferred embodiment, the pharmaceutical composition of the invention comprises from about 5 to about 50% by weight of ethanol, more preferably from about 10 to about 30% weight of ethanol. In most preferred embodiments, the pharmaceutical composition of the invention comprises about 20% by weight of ethanol.
Several materials identified as carriers have also been found to be effective co- solubilizers, either alone or in combination with other viscosity-reducing agents, or certain other carriers. In general, any solvent in which paclitaxel or other taxanes are at least moderately soluble at body temperature or with gentle heating can be used as a co-solubilizer in the vehicle of the novel compositions. Preferred co-solubilizers are those in which at least 25 mg/ml of paclitaxel or other taxane can be solubilized at about 20-25 °C. Some embodiments of the invention comprise more than one co-solubilizer. In some preferred embodiments, the compositions of the invention include at least two solubilizers.
A "surfactant" according to the invention is an amphiphilic moiety having a surface- active group capable of maintaining and/or promoting the dispersion of an hydrophobic compound within an aqueous media. Surfactants suitable in the compositions of the invention are well known in the art. Preferred surfactants include Vitamin E (e.g. alpha-tocopherol) and beta-carotene.
In another aspect of the present invention, the carrier is pretreated with the metal salt prior to preparing the final taxane composition. Thus, the metal salt may or may not be present in the final composition. In a preferred embodiment, the carrier and the metal salt are added together and the resultant solution (dispersion) is heated, typically at a temperature from about 30°C to about 60°C for a time generally in the range of from about 30 minutes to about 8 hours. In another preferred embodiment, the carrier is applied to a matrix such as column containing the metal salt. Columns containing metal salts are prepared by filling a suitable column with a metal salt. Columns of any size can be used in the present invention. However, the column is preferably between 10 cm and 2 meters in length and between 1 cm and 30 cm in diameter. Generally the metal salt has a particle size of between 0.1 μm and 3 mm in diameter, preferably between 1 μm and 1 mm. In a more preferred embodiment, the carrier is treated by passing it through the metal salt column at a rate of between 0.1 ml/min and 500 ml/min, preferably at a rate of between 1.0 ml/min and 200 ml/min. For example, 18 g ferrous sulfate is packed into an empty HPLC steel column 250 mm x 4.6 mm, Cremophor EL is pumped through the packed column at a flow rate of approximately 0.2 mlJmin. The treated Cremophor EL is then used in the taxane formulation.
In another embodiment, the pretreatment with the metal salt is performed in conjunction with another pretreatment with activated charcoal. Activated charcoal is commercially available from several sources e.g., Calgon (Pittsburg, PA) and Spectrum Chemical Manufacturing Corp. (Gardena, CA). Alternatively, charcoal may be activated in accordance with standard procedures, notably by chemical treatment, or steam or some other heat source, charcoal can be "activated". Bonhomme-Faivre, et al., Life Sci. 6'6Y°):817-827 (2000), for example, discloses pinewood charcoal LSM (CECA-SA, 92 La Defense) and peat charcoal SX4 (Norit 93, Le Blanc Masnil), activated by steam and washed with phosphoric acid. The surface absorption for pinewood charcoal is 1,000 m2/g and 650 m2/g for peat charcoal. In general, the activated charcoal has a surface area ranging from about 500 to about 1300 m /g (including sub-ranges thereof), and preferably a median surface area range of about 900 m /g. One method of treating taxane carriers such as castor oils with charcoal is described in International patent publication WO 00023070.
In a preferred embodiment, a predetermined amount of the carrier is added together with activated charcoal to produce a suspension of the charcoal in the carrier. The product is thus a free suspension of the activated charcoal. Persons skilled in the art will be able to determine the amounts of activated charcoal in order to remove impurities, in accordance with standard techniques. In general, the charcoal is present in the suspension in an amount of from 3 to about 20% (w/w), preferably from about 5 to about 10 % (w/w), including sub- ranges thereof. The carrier and activated charcoal are allowed to remain in contact under conditions (e.g., time and temperature) to allow removal or capture of impurities by the charcoal. Although not intending to be bound by any particular theory of operation, it is believed that the activated charcoal adsorbs the impurities. In preferred embodiments, the suspension is heated, generally at a temperature of from about 30°C to about 60°C, and for a period of time from about 1 to about 6 hours, including sub-ranges thereof. It is believed that the heating enhances absorption of impurities and thus facilitates their removal from the carrier. It is also preferred to stir the suspension, at least periodically. The activated charcoal is then separated from the carrier. This separation is conveniently performed by at least one filtration step. In the event that two or more filtration steps are used, filters having
successively smaller apertures are used. In preferred embodiments, the heated suspension is filtered while it is still heated. It is believed that the lesser viscosity of the heated suspension facilitates filtration. In less preferred embodiments, the heated suspension is allowed to cool to about room temperature, optionally with stirring. Other techniques for separating or removing activated charcoal are known in the art.
The taxane in the formulations of the present invention exhibits reduced solvolysis of an ester side chain at C-13, reduced deacetylation at C-10, and/or reduced epimerization at C- 7 thereof. Accordingly, the stabilization of a taxane provided by a metal salt may be determined by the extent of the reduction of one or more known degradation products (e.g., 7- epi-taxol C, 10-decetyl taxol, 7-epi-taxol, 7-epi-10-deacetyl-taxol, baccatin III, 10- deacetylbaccatin III, cephalomannine, nitine, 7-epi-cephalomannine. These determinations can be made in accordance with known procedures. See, for example, Miller et al, J. Org. Chem. 46: 1469-1474 (1981) and Volk et al, J. of Chromatography B 696:99-115 (1997).
A bioavailability enhancing agent can also be used in conjunction with the formulations of the present invention. See U.S. Patent 5,968,972 to Broder, et al. A bioavailability-enhancing agent may be administered before, at the same time, or immediately after the administration of the compositions of the invention. Accordingly, in some preferred embodiments of the invention, the pharmaceutical compositions include a bioavailability- enhancing agent. In general, the dosage range of the bioavailability-enhancing agent to be co-administered with the taxane in accordance with the invention is from about 0.1 to about 20 mg/kg of patient body weight, preferably from about 3 to about 15mg/kg of patient body weight, and more preferably from 5-10 mg/kg.
The present invention is intended for use with any mammal that may benefit from the compositions of the present invention. Foremost among such mammals are humans, although the invention is not intended to be so limited, and is applicable to veterinary uses. The compositions are useful in the treatment of both malignant and non-malignant diseases.
Reference is made herein to various methodologies and materials known to those of skill in the art. Standard reference works setting forth the general principles of pharmacology include Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9 Ed.,
McGraw Hill Companies Inc., New York (1996). Standard reference works setting forth the general principles of modern pharmaceutics (Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, Mack Publishing Co., Easton, PA (1990) and Remington: The Science and Practice of Pharmacy, Lippincott, Williams & Wilkins (1995)). The following examples are intended to further illustrate certain preferred embodiments of the invention and are not limiting in nature. These examples are not intended, however, to limit the invention in any way or to set forth specific active ingredients, carriers, co-solubilizers, enhancing agents, dosage ranges, testing procedures or other parameters which must be used exclusively to practice the invention. Hence, for example the use of paclitaxel to illustrate aspects of taxanes as a whole is purely for illustrative purposes and should not be construed as limiting the invention.
EXAMPLE 1 Stability Tests of Paclitaxel in Pretreated Cremophor EL The stabilizing effect of coordinating metal salts, such as zinc, copper and ferrous sulfate or gluconate, on paclitaxel in an EtOH/EL (50:50) formulation (6 mg/mL) was examined. Salt columns were used to treat Cremophor EL before being added to paclitaxel formulations, which was then analyzed after being subjected to stress (24 hours at 80°C).
Paclitaxel formulation (6 mg/mL) in Cremophor EL/EtOH (50:50) was used as the control. It was prepared by (1) adding 60 mg of paclitaxel bulk powder and 3 ml absolute ethanol to a 10 ml volumetric flask, (2) swirling and gently warming the flask until complete dissolution of the paclitaxel powder, (3) adding 5.27 g Cremophor EL to the solution, and (4) diluting the resulting mixture to a final volume of 10 ml with absolute ethanol.
The metal salt formulations were prepared in a similar manner as the control, except step (3). Instead of adding 5.27 g Cremophor EL to the solution, the Cremophor EL was suspended in about 5 ml of ethanol and the Cremophor EL suspension was stirred over the metal salt, i.e., zinc gluconate, ferrous gluconate, copper gluconate, or ferrous sulfate, for 4 hours at 45°C. The Cremophor EL suspension was then filtered and added to the 10 ml volumetric flask to prepare paclitaxel formulation. The paclitaxel samples and the control
were tested for thermal stability by treating the samples at 80°C for 24 hours. The stability tests of these paclitaxel formulations are shown in Table 1 below.
TABLE 1 STABILITY PROFILE (80°C - 24 HOURS) Paclitaxel in Cremophor EIJEtOH solutions (6 mg/mL). Pretreatment of Cremophor EL.
a Cremophor EL stirred over salt 4 hours @ 45°C, filtered and used for preparation of Paclitaxel formulation.
"b The standard entry shows the impurity profile of the starting paclitaxel in ethanol - not exposed to stress conditions.
The data in Table 1 show that in the presence of Zn2+ Gluconate, the degradation of paclitaxel in the formulation was less than 7.5% after being exposed to a temperature of 80°C for 24 hours. Similarly, the presence of Fe2+ Gluconate, Cu2+ Gluconate, and FeSO4 reduced paclitaxel degradation to less than 1%, 4% and 3%, respectively after being treated under the same condition. In the absence of metal salts, paclitaxel degradation in the formulation is more than 63% after being exposed to the same condition.
EXAMPLE 2. Stability Tests of Paclitaxel in the Presence of Metal Salts
The control is prepared in the same way as in Example 1.
Paclitaxel composition containing zinc gluconate was prepared by (1) mixing 100 μL of a zinc gluconate solution (100 mg/mL) in H2O with an aliquot (2.0 mL) of a solution (6 mg/mL) of paclitaxel in Cremophor EIJEtOH (50:50), (2) vortexing the resulting suspension for five minutes, and (3) filtering the mixture using a 0.45 μm filter to obtain a clear, colorless solution.
Paclitaxel composition containing Cu2+ Gluconate, Fe2+ Gluconate, Ca2+ Ascorbate, FeSO , A.A 6-Palmitate, or HOCH2SO2Na was prepared in the same way. The paclitaxel samples and the control were subjected to 80°C for 24 hours. Then the paclitaxel degradation was tested. The paclitaxel stability tests results are shown in Table 2.
TABLE 2 STABILITY PROFILE (80°C - 24 HOURS) Paclitaxel in Cremophor EIJEtOH (6 mg/mL) with additives.
a 100 μL of an aqueous solution (100 mg/mL) added to provide 10 mg of salt. b 100 μL of an ethanol solution of Ascorbic Acid 6-palmitate (Ascorbyl palmitate) (100 mg/ml solution) added to provide 10 mg of ester. c The standard entry shows the impurity profile of the starting paclitaxel in ethanol - not exposed to stress conditions.
The data in Table 2 show that in the presence of Fe2+ Gluconate, Cu2+ Gluconate, Zn2+ Gluconate, Ca2+ Ascorbate, FeSO j A.A 6-Palmιtate, or HOCH2SO2Na, degradation of
paclitaxel degradation in the formulation was less than 3%, 3%, 3%, 12%, 12%, 3%, and 5%, respectively after being exposed to a temperature of 80°C for 24 hours. In the absence of metal salts or A.A 6-Palmitate, paclitaxel degradation in the formulation is more than 63% after being exposed to the same condition. EXAMPLE 3
Stability Tests of Paclitaxel in the Presence of Metal Salts and TPGS Paclitaxel formulation (6 mg/mL) in Vitamin E TPGS/EtOH (50:50) was used as control. It was prepared by (1) preparing a working placebo of Vitamin E TPGS/EtOH (50:50) by gently warming a mixture of Vitamin E TPGS and absolute ethanol, (2) adding the placebo (7 mL) to a 10 ml volumetric flask containing paclitaxel bulk powder (60 mg), (3) stirring the mixture at room temperature until complete dissolution of the paclitaxel, and (4) diluting the resulting solution to a final volume of 10 ml with the placebo.
The paclitaxel formulations containing metals salts were prepared by adding various amount of Cu"1"1" Gluconate, Fe++ Gluconate, Zn++ Gluconate, or HOCH2SO2Na to the control formulation. The stability test results were listed in Table 3.
TABLE 3 PACLITAXEL STABILITY (80°C - 24 HOURS) Vit. E TPGS/EtOH Solutions (6 mg/ml).
All salts (5 mg) added as an aqueous solution to the paclitaxel formulation. The paclitaxel standard entry was not subjected to any stress conditions.
The data in Table 3 show that the presence of Cu++ Gluconate, Fe2+ Gluconate, Zn2+ Gluconate, or HOCH2SO2Na, the degradation of paclitaxel in the formulation was less than 1%, 1%, 4%, and 27%, respectively, after being exposed to a temperature of 80°C for 24 hours. In the absence of metal salts, paclitaxel degradation in the formulation is more than 40% after being exposed to the same condition.
EXAMPLE 4 Stability Tests of Paclitaxel in Ascorbyl 6-Palmitate and TPGS Formulation
Paclitaxel formulation (6 mg/mL) in Vitamin E TPGS/PG/EtOH (40:40:20) was used as control. It was prepared by (1) preparing a working solution of the placebo by gently warming a mixture of Vitamin E TPGS, propylene glycol and absolute ethanol (ratio 40:40:20), (2) adding the placebo (7 mL) to a 10 ml volumetric flask containing 60 mg paclitaxel, (3) stirring the mixture at room temperature until complete dissolution of the paclitaxel powder, and diluting the resulting solution to final volume of 10 ml with absolute ethanol.
The paclitaxel formulation containing Ascorbyl 6-Palmitate was prepared by adding Ascorbyl 6-Palmitate to the control formulation. The stability test results were listed in Table 4.
TABLE 4 PACLITAXEL STABILITY (80°C - 24 HOURS) Vit. E TPGS/PG/EtOH Solutions (6 mg/ml).
Ascorbyl palmitate (5 mg) added as an ethanol solution to the paclitaxel formulation. Paclitaxel standard in ethanol not subjected to stress conditions.
The data in Table 4 show that in the presence of Ascorbyl 6-Palmitate, paclitaxel degradation is less than 1% after being exposed to a temperature of 80°C for 24 hours. In the absence of Ascorbyl 6-Palmitate, paclitaxel degradation in the formulation is more than 34% after being exposed to the same condition.
EXAMPLE 5 Paclitaxel Stability Test in the Presence of Zn Methionine The sample is prepared by suspending 100 mg of ZnMet and 60 mg of paclitaxel in 10 ml of a mixture of Cremophor EL and Ethanol. The control is prepared by suspending 60 mg of paclitaxel in 10 ml of a mixture of Cremophor EL and Ethanol. Both the sample and the control are treated 80°C for 48 hours and then tested for paclitaxel stablilities. The stability of paclitaxel in the sample is more than 98% while the stability of paclitaxel in the control is less than 60%. 10 mg of ZnMet and 6 mg of paclitaxel were suspended in a mixture of Cremophor EL and Ethanol. EXAMPLE 6
Pretreatment of Cremophor with Activated Charcoal and Metal Salt
Cremophor El (-400 mL) was pumped through a steel column containing activated charcoal (34 g) at a flow rate of approximately 0.2 mlVmin. The initial eluate (-20 mL) was discarded and the successive fraction (-45 mL) was collected and subsequently passed through a second steel column containing FeSO (18 g). The initial eluate was discarded (-20 mL) and the remainder of material was used to prepare the Paclitaxel formulation for stability analysis. Heating of the paclitaxel formulation (6 mg/mL in 50:50 Cremophor EL - Ethanol) at 70 °C for 72 hours and analysis by HPLC showed 97% unchanged paclitaxel when compared to the control under the same conditions (Paxene™ formulation - 96% unchanged paclitaxel).
As used herein, the term "about" is intended to convey that the numbers and ranges disclosed herein are flexible and that practice of the present invention using temperatures, concentrations, amounts, etc. outside of the range or different from a single value will achieve the desired result. The term typically includes a deviation of ± 10% of any value it modifies.
All patent and non-patent publications cited in this specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All these publications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated as being incorporated herein by reference.
Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific substances and procedures described herein. Such equivalents are considered to be within the scope of this invention.
Claims
1. A composition comprising a taxane, a carrier and a metal salt of an acid.
2. The composition of claim 1 wherein said metal is iron, copper, zinc, calcium, manganese, magnesium, aluminum, tin, lanthanum, cerium, selenium, or titanium.
3. The composition of claim 1 wherein said acid is an alpha- or beta-hydroxy acid.
4. The composition of claim 3 wherein said acid is citric acid.
5. The composition of claim 4 wherein said metal salt is zinc citrate.
6. The composition of claim 3 wherein said acid is gluconic acid.
7. The composition of claim 6 wherein said metal is iron, copper, zinc, calcium, manganese, magnesium, aluminum or titanium gluconate.
8. The composition of claim 1 wherein said acid is hydroxymethylsulfinic acid.
9. The composition of claim 8 wherein said metal salt is iron, copper, zinc, calcium, manganese, magnesium, aluminum, sodium or titanium hydroxymethylsulfinate.
10. The composition of claim 1 wherein said acid metal salt is zinc methionine.
11. The composition of claim 1 wherein the acid is ascorbic acid.
12. The composition of claim 1 wherein the acid is palmitic acid.
13. The composition of claim 1 wherein said taxane comprises paclitaxel or docetaxel.
14. The composition of claim 1 wherein said carrier is a polyethoxylated castor oil.
15. A method of increasing stability of a taxane comprising formulating the taxane, a carrier and a metal salt of an acid into a composition.
16. A method of stabilizing a taxane during storage, comprising: pretreating a carrier with a metal salt of an acid; and formulating the pretreated carrier with the taxane.
17. The method of claim 16 wherein said pretreating comprises heating the carrier and the metal salt.
18. The method of claim 16 wherein said pretreating comprises loading the carrier onto a matrix containing the metal salt, and eluting the carrier therefrom.
19. The method of claim 16 further comprising contacting the carrier or pretreated carrier with activated charcoal.
20. The method of claim 19 wherein said contacting comprises heating a slurry of the carrier and the activated charcoal.
21. The method of claim 16 wherein the carrier comprises a polyethoxylated castor oil.
22. A composition comprising a taxane and a carrier treated in accordance with the method of claim 16.
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US191802P | 2000-03-24 | ||
PCT/US2001/009416 WO2001072300A1 (en) | 2000-03-24 | 2001-03-23 | Uses of metal salts to stabilize taxane-based compositions |
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EP01920712A Withdrawn EP1408956A1 (en) | 2000-03-24 | 2001-03-23 | Uses of metal salts to stabilize taxane-based compositions |
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JP2005515187A (en) * | 2001-11-26 | 2005-05-26 | スーパージェン インコーポレイテッド | Process for the preparation of pharmaceutical compositions using polyoxyethylated castor oil |
CA2471572A1 (en) * | 2001-12-28 | 2003-07-17 | Ivax Research, Inc. | Taxane based compositions and methods of use |
KR100533458B1 (en) * | 2002-07-20 | 2005-12-07 | 대화제약 주식회사 | Composition for solubilization of paclitaxel and preparation method thereof |
AU2002950713A0 (en) | 2002-08-09 | 2002-09-12 | Vital Health Sciences Pty Ltd | Carrier |
US7989490B2 (en) * | 2004-06-02 | 2011-08-02 | Cordis Corporation | Injectable formulations of taxanes for cad treatment |
US20090004166A1 (en) * | 2004-08-03 | 2009-01-01 | Simon Michael West | Carrier For Enternal Administration |
KR100866728B1 (en) * | 2004-11-12 | 2008-11-03 | 주식회사종근당 | The injection of tacrolimus |
EP1690551A3 (en) | 2005-02-10 | 2006-10-18 | Sindan Pharma Srl | Method of purifying a surfactant by ultrafiltration |
WO2006084902A2 (en) * | 2005-02-10 | 2006-08-17 | Sindan Pharma Srl | Method of purifying a surfactant by ultrafiltration |
CA2611592A1 (en) * | 2005-06-17 | 2006-12-21 | Hospira Australia Pty Ltd | Liquid pharmaceutical formulations of docetaxel |
EP2548581A3 (en) | 2005-06-17 | 2013-02-20 | Vital Health Sciences Pty Ltd. | A carrier comprising one or more di and/or mono-(electron transfer agent) phosphate derivatives or complexes thereof |
DK3311805T3 (en) | 2005-08-31 | 2020-04-14 | Abraxis Bioscience Llc | COMPOSITIONS CONTAINING VERY WATER-SOLUBLE PHARMACEUTICAL AND ANTIMICROBIAL AGENTS |
US8512761B2 (en) | 2006-01-27 | 2013-08-20 | Yale University | Fast acting inhibitor of gastric acid secretion |
BRPI0600194A (en) * | 2006-01-30 | 2007-10-23 | Quiral Quimica Do Brasil S A | docetaxel-containing pharmaceutical compositions and a degradation inhibitor and process for obtaining same |
ES2344674B1 (en) | 2008-08-07 | 2011-06-29 | Gp Pharm, S.A. | INJECTABLE PHARMACEUTICAL COMPOSITION OF TAXANOS. |
JO3434B1 (en) * | 2009-07-31 | 2019-10-20 | Millennium Pharm Inc | Pharmaceutical compositions for the treatment of cancer and other diseases or disorders |
US7772274B1 (en) | 2009-10-19 | 2010-08-10 | Scidose, Llc | Docetaxel formulations with lipoic acid |
US8912228B2 (en) | 2009-10-19 | 2014-12-16 | Scidose Llc | Docetaxel formulations with lipoic acid |
US8541465B2 (en) | 2009-10-19 | 2013-09-24 | Scidose, Llc | Docetaxel formulations with lipoic acid and/or dihydrolipoic acid |
AU2011213557B2 (en) | 2010-02-05 | 2015-05-07 | Phosphagenics Limited | Carrier comprising non-neutralised tocopheryl phosphate |
US8652511B2 (en) | 2010-03-30 | 2014-02-18 | Phosphagenics Limited | Transdermal delivery patch |
CN102970990A (en) | 2010-05-03 | 2013-03-13 | 帝国制药美国公司 | Non-aqueous taxane pro-emulsion formulations and methods of making and using the same |
RU2603833C2 (en) * | 2010-11-08 | 2016-11-27 | Кадила Фармасьютикалз Лимитед | Pharmaceutical composition of taxoids |
US9561243B2 (en) | 2011-03-15 | 2017-02-07 | Phosphagenics Limited | Composition comprising non-neutralised tocol phosphate and a vitamin A compound |
JO3685B1 (en) | 2012-10-01 | 2020-08-27 | Teikoku Pharma Usa Inc | Non-aqueous taxane nanodispersion formulations and methods of using the same |
JP6360881B2 (en) | 2013-03-22 | 2018-07-18 | ミレニアム ファーマシューティカルズ, インコーポレイテッドMillennium Pharmaceuticals, Inc. | Combination of catalytic MTORC1 / 2 inhibitor and selective inhibitor of Aurora A kinase |
JP6882321B2 (en) | 2015-12-09 | 2021-06-02 | フォスファージニクス リミテッド | Pharmaceutical product |
BR112019012946A2 (en) | 2016-12-21 | 2019-11-26 | Avecho Biotechnology Ltd | process |
CN110585189B (en) * | 2019-09-05 | 2022-12-30 | 广东艾时代生物科技有限责任公司 | Application of cephalomannine in preparation of medicines for treating malaria |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
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TW406020B (en) * | 1993-09-29 | 2000-09-21 | Bristol Myers Squibb Co | Stabilized pharmaceutical composition and its method for preparation and stabilizing solvent |
US5919815A (en) * | 1996-05-22 | 1999-07-06 | Neuromedica, Inc. | Taxane compounds and compositions |
KR19990075621A (en) * | 1998-03-23 | 1999-10-15 | 임성주 | Inclined Plate Culture Tank |
CN1225262A (en) * | 1998-12-09 | 1999-08-11 | 延边香料研究所 | Anti cancer drug contg. taxals alcohol |
US6136846A (en) * | 1999-10-25 | 2000-10-24 | Supergen, Inc. | Formulation for paclitaxel |
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2001
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- 2001-03-23 AR ARP010101395A patent/AR027715A1/en not_active Application Discontinuation
- 2001-03-23 WO PCT/US2001/009382 patent/WO2001072299A1/en not_active Application Discontinuation
- 2001-03-23 CA CA002404370A patent/CA2404370A1/en not_active Abandoned
- 2001-03-23 JP JP2001570261A patent/JP2003528142A/en active Pending
- 2001-03-23 EP EP01920699A patent/EP1315484A1/en not_active Withdrawn
- 2001-03-23 JP JP2001570260A patent/JP2003528141A/en active Pending
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---|
See references of WO0172300A1 * |
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